Rapid mapping of language function and motor function without subject participation

ABSTRACT

Provided is a method for mapping a neural area involved in speech processing, including applying a plurality of recording electrodes to a surface of a cortex of a human subject, presenting a plurality of auditory stimuli to the subject wherein some of the plurality of stimuli are speech sounds and others of the plurality of auditory stimuli are non-speech sounds, recording brain activity during the presenting of the plurality of auditory stimuli, and identifying one or more brain areas wherein activity changes more after presentation of speech sounds than it does after presentation of non-speech sounds, wherein the human subject does not speak during the presenting and the recording. Also provided is a method for mapping a neural area involved in speech production wherein the human subject does not speak during presenting speech stimuli and recording neural activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/570,927, filed on Oct. 31, 2017 as a U.S. national stage filing undersection 371 of International Application No. PCT/US2016/0030418 filedMay 2, 2016, published in English on Nov. 10, 2016 as WO2016/179094A1,which claims priority under 35 U.S.C. § 119 to U.S. ProvisionalApplication No. 62/156,237, filed May 2, 2015, and U.S. ProvisionalApplication No. 62/156,422, filed May 4, 2015, all of which foregoingapplications are herein incorporated by reference in their entireties.

GOVERNMENT RIGHTS STATEMENT

This invention was made with government support under EB000856 andEB018783 awarded by the NIH, and W911NF1410440 awarded by the ARMY/ARO.The government has certain rights in the invention.

FIELD OF THE INVENTION

The present invention relates to, inter alia, rapid mapping of languagefunction and motor function without subject participation.

BACKGROUND OF THE INVENTION

Mapping areas of individuals' brains that are responsible for processinglanguage, sensory, motor, or other functions can be done by measuringbrain waves and asking subjects to participate in various tasks, such asthose related to linguistic or motor functions. Neural activity elicitedby presentation of sensory stimuli, such as tactile or auditory, alsosignify brain regions involved in processing such stimuli and/orproducing behavioral responses thereto. However, currently availablemethodologies for such mapping are hampered by various limitations, suchas the need for subject responsiveness during mapping. For example,electrical cortical stimulation, a widely used measure for brainmapping, conventionally works by assessing the effect of electricalstimulation (ECS) of distinct brain regions on a subject's behavior,where effects of stimulation indicates that the stimulated region playsa function in such behavior. For certain behaviors and subjects,however, ECS is not useful as a brain mapping technique, such as wheresubjects may be incapable of or poor at the given behavior at baseline(e.g., speech and aphasic subjects, or musculoskeletal responses inparalyzed subjects). ECS also poses risks, including the unintentionalinduction of seizures.

Functional language or sensorimotor mapping for peri-operative planning,such as with regard to surgical removal of brain tumors or epileptogenicneural tissue, is of utmost importance given the high variability instructural anatomy and function across individuals. For example,structurally, essential language cortex can occupy from 1 cm² to greaterthan 6 cm². Functionally, classical Wernicke's region, consideredimportant for processing and interpreting received language stimuli,varies substantially, since it is the highest common receptive languagenode in only 36% of people. Similarly, only 79% of people have aclassically defined Broca's area, which is considered to be responsiblefor initiating and controlling the expression of language. Broca's area(expressive language) consists of the pars triangularis and parsopercularis of the inferior frontal gyms, while Wernicke's area(receptive language) encompasses a region of the posterior superiortemporal gyms. The two regions are connected through the arcuatefasciculus, likely with involvement of other white matter tracts. Inorder to avoid inadvertent interference with language or sensorimotorfunctions by surgical resection of brain tissue responsible forcontrolling these functions, it is therefore necessary to map, for theindividual patient, precisely what region or regions of the cortex areresponsible for controlling them such that they can be avoided duringresection or other procedures. There is therefore a need for an improvedmethod for mapping neural regions responsible for particular functions,such as language or sensorimotor function.

SUMMARY OF THE INVENTION

The present invention relates to, inter alia, a method for mapping aneural area involved in speech processing, including applying aplurality of recording electrodes to a surface of a cortex of a humansubject, presenting a plurality of auditory stimuli to the subjectwherein some of the plurality of stimuli are speech sounds and others ofthe plurality of auditory stimuli are non-speech sounds, recording brainactivity during the presenting of the plurality of auditory stimuli, andidentifying one or more brain areas wherein brain activity of the one ormore brain areas changes more after presentation of speech sounds thanit does after presentation of non-speech sounds, wherein the humansubject does not speak during the presenting and the recording.

In another aspect, the present invention relates to, inter alia, amethod for mapping a neural area involved in speech production includingapplying a plurality of recording electrodes to a surface of a cortex ofa human subject, presenting a plurality of auditory stimuli to thesubject wherein some of the plurality of stimuli are speech sounds andothers of the plurality of auditory stimuli are non-speech sounds,recording brain activity during the presenting of the plurality ofauditory stimuli, and identifying one or more brain areas wherein brainactivity of the one or more brain areas changes more after presentationof speech sounds than it does after presentation of non-speech sounds,wherein the human subject does not speak during the presenting and therecording.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating aspects of the present invention, thereare depicted in the drawings certain embodiments of the invention.However, the invention is not limited to the precise arrangements andinstrumentalities of the embodiments depicted in the drawings. Further,as provided, like reference numerals contained in the drawings are meantto identify similar or identical elements. The foregoing and otherobjects, features, and advantages of the invention are apparent from thefollowing detailed description taken in conjunction with theaccompanying drawings in which:

FIG. 1 is a schematic diagram of major cortical regions involved inlanguage processing, and major pathways between them.

FIG. 2A is a topographical mapping showing placement of recordingelectrodes in a subject whose neural activity while the subject wasawake was recorded.

FIG. 2B is a topographical mapping showing placement of recordingelectrodes in a subject whose neural activity while the subject wasawake was recorded.

FIG. 2C, FIG. 2D, FIG. 2E, and FIG. 2F are graphs illustrating theresults for receptive language mapping from various electrodes in apatient while awake and under anesthesia.

FIG. 3A is a topographical mapping showing placement of electrodes in asubject administered ECS for language mapping while awake andelectrocorticography (ECoG) for language mapping while anesthetized.

FIG. 3B is a graph illustrating the results of ECoG recording from anelectrode demonstrating responsiveness to speech sounds in ananesthetized subject.

FIG. 4A, FIG. 4B, and FIG. 4C are diagrams and charts illustrating ECSand ECoG electrode placement and language area mapping results fromthree different patients.

FIG. 5 shows a magnetic resonance (MR) image demonstrating the presenceof a tumor in a subject (left) and functional magnetic resonance imaging(fMRI) showing the proximity of Broca's area to the tumor (right).

FIG. 6A and FIG. 6B show an 8×8 cm grid of 64 electrodes and itssubdural placement on a subject's cortex, respectively.

FIG. 6C and FIG. 6D show a 2.5×2.5 cm grid of 64 electrodes and itssubdural placement on a subject's cortex, respectively.

FIG. 7A shows electrode contacts of the standard subdural grid coveragein a subject with a tumor, whose location is indicated by blue shading.

FIG. 7B Functional MRI showing increased BOLD activity (shown in yellowand orange) in Broca's area, as well as auditory/Wernicke's area,precentral gyms, supplementary motor/premotor cortex and prefrontalcortex.

FIG. 7C Electrode contacts of a standard extraoperative subdural grid,and results from extraoperative ECoG-based functional language areamapping (shown in green) demonstrating increased activity in Boca'sarea, precentral gyms, supplementary motor/premotor cortex andpostcentral gyms.

FIG. 7D shows results from intraoperative ECoG-based functional languagemapping.

FIG. 8 is diagrams illustrating the result of ECoG-based brain mappingof brain areas responsible for sensory function of the index finger in asubject.

DETAILED DESCRIPTION OF THE INVENTION

Aspects of the present invention and certain features, advantages, anddetails thereof, are explained more fully below with reference to thenon-limiting embodiments illustrated in the accompanying drawings.Descriptions of well-known materials, fabrication tools, processingtechniques, etc., are omitted so as to not unnecessarily obscure theinvention in detail. It should be understood, however, that the detaileddescription and the specific examples, while indicating embodiments ofthe invention, are given by way of illustration only, and are not by wayof limitation. Various substitutions, modifications, additions and/orarrangements within the spirit and/or scope of the underlying inventiveconcepts will be apparent to those skilled in the art from thisdisclosure.

The present invention relates to, inter alia, methods, devices, andsystems for mapping areas of the brain responsible for variousfunctions, such as receptive language functions (i.e., receiving,perceiving, interpreting, and/or understanding verbal communication suchas spoken words), expressive language or language production (e.g.,creating and/or producing verbal language such as orally), andsensorimotor processing (e.g., sensing and perceiving tactilestimulation and causing movement of a part or parts of the body). Thereare various methodologies currently available for detecting activity inregions of the brain in response to presentation of various modalitiesand/or cognitive or behavioral responsiveness to stimuli includingcommands or instructions. Among the most sensitive and accurate is ECoG,which entails placement of recording electrodes on the surface of thebrain. Herein, ECoG and describing placement of electrodes on the brainincludes both subdural placement of electrodes, where electrodes areplaced directly on the surface of the brain (i.e., the dura mater is notbetween an electrode and the surface of the brain) and epiduralplacement of electrodes (i.e., electrodes are placed on the dura matersuch that the dura is between an electrode and the surface of thebrain). Brain waves across a full spectrum of frequencies, includingfrom approximately 0.5-4 Hz (delta waves), to approximately 4-8 Hz(theta waves), to approximately 8-12 Hz (alpha waves), to approximately12-40 Hz (beta waves), to above approximately 40 Hz (gamma waves).

As opposed to fMRI or ECS, ECoG does not require electrical stimulationof the brain, permits measurement of neural activity in real time, canbe employed in a surgical theater without the need for an fMRI machine,and does not carry a risk of stimulation-induced seizure. An array ofrecording electrodes may be placed over a region generally known orbelieved to play a role in a certain function, the performance of thefunction by the subject elicited (be the function involved in receptionof stimuli, interpretation of language, cognitive ability, or behavioralor language production). By observing brain waves detected by theelectrodes and determining changes in activity detected by differentelectrodes during a time frame corresponding to the elicitation offunction (e.g., during a period of exposure to speech sounds or tactilestimuli), specific locations of the brain responsible for such functionscan be identified and distinguished from uninvolved regions with a highdegree of spatial resolution.

For certain functions, however, it has conventionally been difficult touse ECoG or other mapping techniques to map the brain in certaincircumstances, such as with particular subjects and particularfunctions. One such example is language mapping during surgery. Forexample, it is sometimes necessary to remove a tumor or epileptogenicregion from the brain surgically. Preferably, a surgeon should avoiddamaging brain regions responsible for particular functions (such aslanguage, or sensorimotor functioning) if possible when resecting atumor or other diseased or disease-inducing tissue, lest these functionsbecome temporarily or permanently impaired by the surgery. However,given the inter-individual heterogeneity of localization of certainfunctions, determining precise neural localizations of functions isdifficult or impossible if based solely on the visual inspection oflandmarks visible on the surface of the brain, it is difficult orimpossible to know without performing brain mapping what specificregions are responsible for these functions in a given subject.

In accordance with an embodiment of the improvements disclosed herein,rapid mapping of language function and motor function in the brain of asubject may be performed. More particularly, rapid mapping can beperformed passively, in that the mapping does not require activeparticipation from the subject. Therefore, the systems and methods ofthe present invention provide a means for conducting brain mapping of asubject before and/or during brain surgery in order to identify areas ofa brain that relate to either language function or motor function. Suchinformation can be conducted without requiring the subject to activelyrespond to stimuli to trigger language or motor functional responses.This information can be important for a surgeon conducting brain surgery(e.g., brain tumor removal or epileptogenic tissue removal), as languageand motor function are two of the most important functions that asurgeon would want to leave intact post-surgery. As such, the presentinvention provides systems and methods to aid in brain surgery. As usedherein, “motor function” also includes “sensory function.” Other aspectsof the present invention are further described herein.

In one aspect of the invention, improved mapping of anesthetizedsubjects (i.e., subjects who are under the influence of anesthesia, suchas intraoperatively, during a period of neural mapping) is provided.However, the invention applies equally well to neural mapping ofsubjects who are non-responsive for reasons other thananesthesia-induced unconsciousness, who are conscious but incapable ofproviding oral or other sensorimotor responses, or who are awake andcapable of responding but for particular reasons elicitation of suchresponsiveness is undesirable for a given application. In one aspect,the present invention provides a method for rapid mapping of languagefunction of a subject, said method comprising steps as disclosed and/orcontemplated herein.

In one embodiment of this method, mapping may be performed withoutactive participation from the subject. In another embodiment, mappingmay be performed before and/or during a brain surgical procedure beingconducted on a subject. In a further embodiment, mapping may inform asurgeon or medical practitioner conducting a brain surgical procedure ofregions of a subject's brain relating to language function. In anotherembodiment, mapping may involve use of electrodes applied to a subject'sbrain. In another embodiment, mapping may involve use of electrodesapplied to a subject's brain and a computer for providing output withrespect to language function. In a further aspect, provided is a systemfor rapid mapping of language function of a subject, said systemcomprising aspects, devices, and/or apparatuses as disclosed and/orcontemplated herein.

In one embodiment, a system is provided in which aspects, devices,and/or apparatuses of the system may enable mapping to be performedwithout active participation from a subject. In another embodiment, asystem is provided wherein aspects, devices, and/or apparatuses of thesystem enable mapping to be performed before and/or during a brainsurgical procedure being conducted on a subject. In a further embodimentaspects, devices, and/or apparatuses of a system enable mapping toinform a surgeon or medical practitioner conducting a brain surgicalprocedure of regions of a subject's brain relating to language function.In another embodiment, aspects, devices, and/or apparatuses of a systeminclude electrodes applied to a subject's brain. In another embodiment,aspects, devices, and/or apparatuses of a system include electrodesapplied to a subject's brain and a computer for providing output withrespect to language function.

In another aspect, provided is a method for rapid mapping of motorfunction of a subject, said method comprising steps as disclosed and/orcontemplated herein. In one embodiment, mapping may be performed withoutactive participation from a subject. In another embodiment, the mappingmay be performed before and/or during a brain surgical procedure beingconducted on a subject. In a further embodiment, mapping informs asurgeon or medical practitioner conducting a brain surgical procedure ofregions of the brain of a subject relating to motor function. In anembodiment, mapping involves use of electrodes applied to a subject'sbrain. In a further embodiment, mapping involves use of electrodesapplied to a subject's brain and a computer for providing output withrespect to motor function.

In another aspect, provided is a system for rapid mapping of motorfunction of a subject. In an embodiment, aspects, devices, and/orapparatuses of a system enable mapping to be performed without activeparticipation from a subject. In another embodiment, aspects, devices,and/or apparatuses of a system enable mapping to be performed beforeand/or during a brain surgical procedure being conducted on a subject.In a further embodiment, aspects, devices, and/or apparatuses enablemapping to inform a surgeon or medical practitioner conducting a brainsurgical procedure of regions of the brain of a subject relating tomotor function. In another embodiment, aspects, devices, and/orapparatuses of a system include electrodes applied to a subject's brain.In another embodiment, the aspects, devices, and/or apparatuses of asystem include electrodes applied to a subject's brain and a computerfor providing output with respect to motor function.

Provided is a method for identifying neural areas responsible forlanguage and/or sensorimotor function without requiring participation ofa subject. As disclosed herein, a method allows for identifying neuralregions responsible for receptive language functions (for example,within Wernicke's area), expressive language functions (for example,within Broca's area), and/or different portions of sensory and/or motorcortex responsible for specific body regions. Surprisingly, and incontrast to conventional techniques and literature, a method is providedfor mapping receptive and expressive language functions in subjectswithout requiring their participation, including if they areunconscious, such as if they are under the influence of surgicalanesthesia at the time brain mapping of such functions is performed.Such method is real-time, allows rapid mapping, and can be performedduring a same surgical procedure during which other surgical procedures,such as a resection, are performed, in the same surgical suite, andafter a subject has been anesthetized without requiring bringing themout of anesthesia for mapping.

Shown in FIG. 1 are several brain regions involved in languageprocessing, including early auditory cortex, and receptive languagefunction. Some of these regions show changes in neural activity uponexposure to auditory stimuli generally, such as early auditory cortex.Others, such as those involved in receptive language function (e.g.,Wernicke's area) preferentially respond to speech and speech-like soundscompared to non-speech sounds. Receptive language areas may show analteration in activity throughout the duration of presentation of aspeech stimulus. Other areas, such as expressive speech (e.g., Broca'sarea) may be particularly active during production of speech. Asdisclosed herein, at certain time points during presentation of speechor speech-like sounds, expressive areas preferentially show alterationsof activity in response to presentation of speech or speech-like soundscompared to presentation of non-speech-like sounds, even when a subjectis not producing speech in response to receipt of the speech stimulus.Furthermore, such responses are detectable in anesthetized subjects,enabling real-time brain mapping during surgery without requiringawakening a patient.

In one aspect, recording electrodes are placed on exposed cortex,including in a region generally predicted to be early auditory cortex,receptive language, and/or expressive language in function, and auditorystimuli are presented. Some auditory stimuli consist of speech sounds,whereas others are scrambled speech possessing acoustic characteristicsof speech but not consisting of words (i.e., scrambled speech). Suchauditory stimuli are presented to a subject and brain waves, such asbroadband gamma waves, are recorded. Production of speech or otherbehavioral responsiveness to speech or other auditory stimulation arenot required of the patient. Alterations in neural activity detected byan electrode during presentation of speech stimuli, wherein suchalterations are not seen or are demonstrably diminished in response topresentation of non-speech or scrambled speech sounds, signify that thebrain region from which the electrode records brain activity is involvedin speech processing, particularly if the electrode has been placed inthe general region where receptive and expressive language functions areknown to be effectuated.

Brain wave impulses detected by an electrode may be passed through afilter, rendered digitally by a computer or processor, and transformedinto stimuli perceptible to a physician or other medical care provideror other trained personnel with skill the field of brain mappingaccording to known methodology. Such individual may observe neuralactivity rendered by such a system to identify regions recorded byelectrodes evincing changes in activity in response to speech stimuli,including differential responsiveness to speech and non-speech stimuli.An electrode whose trace recording demonstrates such differentialresponsiveness signifies where speech function may be processedneurally.

A processor or computer may also may be used to control and/or recordthe time of stimulus onset and the time of stimulus cessation, andprovide an indication of such initiation, cessation, and duration ofstimulus presentation, as well as what type of stimulation (speech ornon-speech) is presented, concurrently with the perceptible rendering ofneural activity. In such manner, a skilled person would be enabled tocompare whether and how much neural activity changes in a given region,and in response to what type of stimulus, to the presence of speech andnon-speech stimuli. For example, a visual trace may be presented ofactivity detected by an electrode when no stimulation is presented,another when a non-speech auditory stimulus is presented (e.g.,optionally, scrambled speech), and another when a speech stimulus ispresented, with all three traces superimposed over each other,synchronized (for the non-speech- and speech-related traces) around whenpresentation of an auditory stimulus was initiated (or terminated, orany particular time point or sampling period after initiation ortermination as may be desired or advantageous for mapping particularfunctions). Such method would permit comparison of how a region comparedin response to different stimuli.

A computer or processor may further store instructions for screeningresponses detected from an electrode. For example, a processor maycontain processing instructions for comparing a filtered digitized traceagainst a threshold level of change in activity that signifiesactivation, either absolutely or when sampled at an advantageous timepoint or period of time with respect to an onset or termination of anauditory stimulus. Such processor could also screen for differences inresponsiveness detected by an electrode to speech and non-speechstimulus. In this way, a system in accordance with the presentdisclosure may support automated detection of a brain region that mayactivated by presentation of speech stimuli (i.e., shows a change inactivity above baseline that exceeds a minimum threshold predeterminedto characterize a responsive region), that may specifically be involvedin speech processing (i.e., shows such change in response to speechsounds but not non-speech sounds, or shows a difference inresponsiveness to such sounds that exceeds a particular threshold thatsignifies differential responsiveness), and/or shows any of the abovethroughout the duration of presentation of a speech sound or only atspecific intervals or periods (e.g., during a pre-specified windowfollowing initiation of speech sound presentation or cessation thereof).

Multiple electrodes may be placed on a subject's brain and recorded fromsimultaneously. For example, arrays of pluralities of electrodes may beplaced over a brain region or regions and recorded from simultaneously.During a surgical procedure, time may be extremely limited and rapidprocessing of information may be essential for a successful operationand health of and recovery by a patient. Use of arrays of pluralities ofelectrodes exponentially increases the amount of information and thenumber of brain regions that can be sampled in a given time frame andexpedites identification of brain regions responsible for particularfunctions. In addition, simultaneous computer processing of wave tracesfrom multiple electrodes enables a rapidity of analysis that may not bepossible absent such processor and may not be feasible without suchprocessor depending on the time pressures attendant a given procedure.For example, a processor could automatically screen input from an arrayof 64 electrodes, or multiple such arrays, and signify a smaller numberfor attention by a skilled practitioner, obviating the need for scrutinyof traces recorded by every electrode.

Some language processing areas may respond throughout one, two, or moreseconds of presentation of speech stimuli. For example, a receptivespeech area (e.g., Wernicke's) may respond for however so long a speechstimulus is presented. Other areas responsible for speech processing,such as expressive speech areas (e.g., Broca's area), may show alteredresponsiveness only during a limited portion of time during which aspeech stimulus is presented. As one, non-limiting example, an electrodeplaced over Broca's area may detect a change in activity during between250 ms and 740 ms after onset of a speech stimulus even though thespeech stimulus may continue to be presented following this time period.Or, such change may be detected during between 100 ms and 1000 ms afterstimulus onset, 10 ms to 250 ms after stimulus onset, 750 ms and 1000 msafter stimulus onset, 300 ms or 800 ms after stimulus onset, or between100 ms and 1000 ms after onset of speech stimulus presentation, or someother time-delimited period during but not coextensive with the periodduring which a speech stimulus is presented. All of the foregoing maycharacterize responsiveness of electrodes on the brain of a subject whois under anesthesia throughout the entire period or stimuluspresentation and response recordation. Such changes in responsivenesscould be broadband gamma activity, but theta, delta, alpha, or betaactivity may also be observed and indicative of altered responsivenessto stimulation.

Any size of electrode and inter-electrode spacing, or size or shape ofelectrode array may be used in accordance with the present disclosure.Electrodes may have an exposed surface, for measuring neural activity,of approximately 1 mm or less, or between approximately 1 mm andapproximately 2.5 mm, or between approximately 2.5 mm and 5 mm, orlarger. They may be spaced from each other by approximately 5 cm orless, 2.5 cm or less, 1 cm or less, 500 mm or less, 100 mm or less, 10mm or less, 5 mm or less, or 3 mm or less, approximately.

Examples

In one example, patients passively listened to 32 words and 32 non-wordswhile awake and under anesthesia and neural activity was measured viaECoG. A minimum of 4 runs for each condition (at least 128 words and 128non-words) were presented. The auditory stimuli consisted of 32 wordsand 32 unintelligible non-words, i.e. sounds that match the words induration, intensity, temporal modulation, and power spectrum but are notintelligible. See Canolty et al. (2007) Frontiers in Neuroscience, 1:14.Both types of stimuli activate the primary auditory cortex. A blockconsisted of a 20 s baseline followed by the 64 stimuli randomlyinterleaved. Each block had a duration of approximately 2 min. Thesounds were presented via earphones placed in the ears of the patientduring the surgical prepping. Two blocks were presented while thepatient is still awake and used as a control for the coverage ofWernicke's area. A minimum of four blocks were then presented followingthe sedation of the patient with propofol. A general predicted vicinityof Wernicke's area was located using known methodology, includingvisualizing landmarks on the brain surface as is well-known in thefield. We locations corresponding to Wernicke's area were stimulated toinduce cortico-cortical evoked potentials (CCEPs) in Broca's area usingwell-known protocols. See Matsumoto et al. (2004) Brain, 127: 2316-30. Aminimum of 50 CCEPs was determined for each location, over less than 1minute for each location with a stimulation frequency of 2 Hz.

Mapping of Wernicke's area was validated under general anesthesia in oneepileptic patient with right hemisphere coverage undergoing the secondstage of a two-stage epilepsy surgery procedure. The electrode grid usedfor stimulation and recording covered the auditory and motor corticesbut not Broca's area (confirmed by an absence of inferior frontalcortical responses during a verb generation task while the patient wasawake). Two blocks were obtained while the patient was awake, and sixwhile under propofol anesthesia. The recorded ECoG signals wereband-pass filtered in the high gamma range (70-170 Hz) and averaged overtrials. Electrode locations for mapping while awake are shown in FIG. 2Aand while anesthetized in FIG. 2B. The results for four differentlocations (channels 41, 79, 44, and 45) are presented in FIGS. 2C-2F,respectively. Time courses for wave traces show the averaged high gammaresponses to words (blue when the patient is awake, black underanesthesia) and non-words (red when the patent is awake, magenta underanesthesia). Time 0 indicates onset of stimulus. Location 44 is situatedin the primary auditory cortex and responds equally to words andnonwords when the patient is awake (FIG. 2E). Location 45 is situatedinferior to the primary auditory cortex, presumably in Wernicke's area.Its response to words is twice larger to its response to non-words (FIG.2F). This dissociation between words and non-words is conserved duringanesthesia despite a delay of the responses and the decrease by a factor2 of their amplitude. (FIG. 2F).

Results for another patient, following the foregoing protocol, arepresented in FIGS. 3A (electrode placement) and 3B (wave traces foraveraged high gamma responses to words, in blue, and non-words, in red,when the patent is under anesthesia). ECoG signals at channel 24 (FIG.3B) clearly respond to the auditory stimulus (words or non-words) thatis presented at time 0, and responds differently for words (blue trace)and non-words (red trace).

Results from three additional subjects (A-C) were obtained in anotherexample. All three subjects were patients at Albany Medical Center(Albany, New York). Subject A was diagnosed with a low-grade glioma inthe left frontal lobe after presenting with new-onset seizures. SubjectsB and C suffered from intractable epilepsy. All subjects underwenttemporary placement of subdural electrode grids to localize seizure fociand eloquent cortex prior to surgical resection. The electrode gridswere approved for human use (Ad-Tech Medical Corp., Racine, WI; and PMTCorp., Chanhassen, MN) and covered different areas within frontal,temporal and parietal lobes of the left hemisphere. All three subjectshad coverage of frontal lobe language areas and two of the three(subjects B and C) also had coverage of temporal lobe language areas.Electrodes consisted of platinum-iridium discs (4 mm in diameter, 2.3-3mm exposed), were embedded in silicone, and were spaced 6-10 mm apart.The total number of implanted electrodes was 61, 98 and 134 in subjectsA-C, respectively. Following subdural grid implantation, each subjecthad postoperative anterior-posterior and lateral radiographs, as well ascomputer tomography (CT) scans to verify grid location. Preoperativelanguage lateralization (LL) had been assessed previously with fMRI insubject A and with WADA testing in subjects B and C. Based on theseevaluations, language was lateralized to the left hemisphere in allthree subjects.

Once subjects recovered postoperatively, ECoG signals were recorded atthe bedside using general-purpose BCI2000 software, which controlledeight 16-channel g.USBamp biosignal acquisition devices (g.tec, Graz,Austria). To ensure integrity of clinical data collection, a connectorsplit the electrode cables into two separate sets. One set was connectedto the clinical monitoring system and another set was connected to theg.USBamp acquisition devices. ECoG signals were amplified, digitized at1200 Hz and stored by BCI2000. Electrode contacts distant fromepileptogenic foci and areas of interest were used for reference andground.

3D cortical brain models were created for each subject by submittingpreoperative high-resolution magnetic resonance imaging (MM) scans toFreesurfer software (http://surfer.nmr.mgh.harvard.edu/). MRI scans wereco-registered with post-operative CT images using SPM software(http://www.fil.ion.ucl.ac.uk/spm/), and the stereotactic coordinates ofeach grid electrode were identified using custom MATLAB scripts (TheMathWorks Inc., Natick, MA). Finally, the cortical surface of eachsubject and ECoG grid locations were visualized using NeuralActsoftware.

Subjects were asked to listen to four short stories narrated by a malevoice (stimulus duration: 17.15-35.70 s; inter-stimulus interval (ISI)of 10 s) that were part of the Boston Aphasia Battery. The stimuli weredigitized at 44.1 kHz in waveform audio file format and binaurallypresented to each subject using in-ear monitoring earphones (12 to 23.5kHz audio bandwidth, 20 dB isolation from environmental noise). Thesound volume was adjusted to a comfortable level for each subject. Thesubjects did not perform any overt task (such as repeating words,generating verbs in response to the words they heard, etc.).

ECoG activations were identified by detecting task-related changes inthe broadband gamma (70-170 Hz) band. Activity in this band has beenshown to be related to the average firing rate of neuronal populationsdirectly underneath an electrode. A large number of studies have shownthat broadband gamma activity increases reliably in task-relatedcortical areas, including locations traditionally thought to be activeduring speech perception.

To identify those locations that responded to auditory stimulation,channels that did not contain clear ECoG signals were first removed(e.g., ground/reference channels, channels with broken connections, orchannels corrupted by environmental artifacts or interictal activity).Of a total of 61, 98 and 134 channels, this left 59, 79 and 132 channelsfor subjects A-C, respectively, that were submitted to subsequentanalyses. In these analyses, the signals were high-pass filtered at 0.1Hz to remove drifts, and signals were rereferenced to a common averagereference (CAR) montage. The results were band-pass filtered in thebroadband gamma band using a Butterworth filter of order 16. The powerof these signals was then obtained by computing the square of theanalytical signal of the Hilbert transform, followed by a low-passfilter at 4 Hz and down-sampling to 120 Hz. Finally, the resultingbroadband gamma power estimates were normalized by subtracting from themthe signal mean calculated from a baseline period (−6 to −0.5 s prior tothe onset of the auditory stimulus) and by dividing them by the standarddeviation of the signal during the baseline period.

Those locations whose ECoG broadband gamma activity following onset ofthe auditory stimulus (i.e., the response period) was different fromthat during the baseline period were then determined. Several studieshave shown that in receptive auditory areas, broadband gamma activityreliably tracks the time course of the envelope of the intensity of theauditory stimulus or speech stimulus. A few isolated reports documenteddiscrete and brief broadband gamma activations in inferior frontalcortex after the onset of an auditory speech stimulus that occurredafter the activations in receptive auditory areas. Based on thesereports, the response period was defined as 250-750 ms following theonset of the auditory stimulus. Then, for each location, the magnitudeof the change in ECoG broadband gamma power that was related to auditorystimulation by calculating the coefficient of determination (Pearson'sr2 value) was determined. Finally, the statistical significance of eachr2 value, i.e., the probability that ECoG broadband gamma samplesdiffered in amplitude between the response and baseline periods, using apermutation test was determined. In this test, the ECoG broadband gammapower time courses were cut into blocks of 500 ms (thereby preservingthe autocorrelation of the signal), the resulting blocks were randomlypermutated, and finally the corresponding random r2 value wascalculated. The permutation step was repeated 1000 times, thusgenerating a distribution of 1000 random r2 values at each location. r2values were considered to be significant at the 95th percentile of thatdistribution (p=0.05, Bonferroni-corrected for the total number ofelectrodes in each subject). The result of this procedure was a set oflocations whose ECoG broadband gamma activity was significantlydifferent between the baseline and the response periods, and henceresponded to the speech stimuli. Amongst the resulting locations, thosethat were situated within inferior frontal cortex were identified. Thisincluded all electrodes whose Talairach coordinate was within x −28 to−55, y −8 to +34, and z 0 to 28, consistent with previous observations.

Standard electrocortical stimulation mapping of expressive speech wasperformed extra-operatively for clinical purposes. The subjects tookpart in two simple tasks commonly used for this purpose: a picturenaming task, during which subjects were asked to verbally namesequentially presented pictures of simple objects, and a verb generationtask, during which subjects had to verbally generate verbs associatedwith simple nouns presented auditorily. Different electrode pairs werestimulated to establish whether a given pair induced disruption ofexpressive language function, e.g., speech arrest or hesitation.Stimulation intensity typically started at 2 mA and was increased inincremental steps of 2 mA until the neurologist observed clinicaleffects, after-discharges, or reached the 10 mA threshold.

Results for subjects A, B, and C are presented in FIGS. 4A, 4B, and 4C,respectively. FIGS. 4A-4C highlight those locations that were identifiedby analyses of the ECoG signals corresponding to the presentation of thespeech stimuli (filled circles), and locations that produced arrest ofexpressive language function using ECS mapping (yellow circles).Locations identified by ECoG mapping included the expected locations(highlighted by gray-filled circles) in superior temporal gyms and/orperi-sylvian areas (all subjects) as well as in premotor and/orsupplementary motor areas (FIGS. 4A and 4C). Consistent with previousobservations, responsive locations on or close to superior precentralgyms were also identified (FIG. 4C). Surprisingly, ECoG-based mappingidentified expressive language locations (highlighted by blue-filledcircles) in inferior frontal cortex (pars triangularis and/or parsopercularis) in subjects A, B, and C, (FIGS. 4A-4C, respectively). FIG.4C also presents exemplary time courses of ECoG broadband gamma activityin Patient C.

ECS mapping identified 1-2 locations in which stimulation producedexpressive language arrest in each subject (FIGS. 4A-4C, yellowcircles). These locations were also located in or around parstriangularis and pars opercularis. ECS-positive sites overlapped withthe sites identified using ECoG or were located no more than one contactaway.

In another example, recordings were made of a 33 year-old male whopresented after a motor vehicle accident while experiencing a first timeseizure. The patient had a computerized tomography (CT) scan as part ofhis initial evaluation that suggested a hypodensity in the left frontallobe. Magnetic resonance (MR) imaging revealed a nonenhancing leftfrontal mass (FIG. 5 , left) and MR spectroscopy characteristicssupported a low-to-medium grade tumor. Given the anatomic location ofthe tumor's proximity to presumed Broca's area, the patient underwentfMRI and diffusion tensor imaging (DTI). The fMRI confirmed the closerelationship of the tumor to Broca's area (within 3-5 mm) with verbgeneration and object naming tasks (p<0.05, family-wise errorcorrection) (FIG. 5 ).

The patient did not have any further seizures after the initiation ofKeppra and he remained neurologically intact without any focal deficitsor aphasia. To comprehensively evaluate expressive language cortex foran optimal postoperative outcome, the patient elected to pursue atwo-staged brain mapping procedure with the use of subdural grids andECS. Prior to surgery, the patient had neuropsychological testing forbaseline evaluation using the Wechsler Adult Intelligence Scale WAIS-IV.The patient gave informed consent through a protocol that was reviewedand approved by the institutional review board of Albany Medical Collegeas well as the US Army Medical and Materiel Command.

For a first stage operation, the patient underwent implantation of an8×8 cm silicon subdural grid embedded with 64 platinum iridiumelectrodes of 4 mm diameter (2.3 mm exposed) and inter-electrodedistance of 1 cm [PMT, Chanhassen, MN] (FIGS. 6A and 6B). Contacts 1, 2and 9 were removed for better contour along the cortical surface.Contact 57 was located most anteriorly, 64 most superiorly and contact 8most posteriorly (FIG. 7A). A four-contact electrode strip was placed onthe skull to provide a ground for the clinical monitoring system. Thepatient tolerated the first stage well and was connected to aNihon-Kohden Neurofax video EEG monitoring system [Tokyo, Japan] thatcontinuously recorded ECoG signals as well as accompanying clinicalbehavior. To ensure integrity of clinical data collection, passivesplitter connectors simultaneously provided ECoG signals to eightoptically isolated and synchronized 16-channel g.USBampamplifier/digitizer units (g.tec, Graz, Austria) with signal sampling at1200 Hz. Clinical review of ECoG signals identified frequent leftfrontal spikes and spike and wave discharges at contact 23.

On postoperative day 2, the patient underwent extraoperative functionalcortical mapping in the epilepsy monitoring unit (EMU) with ECoG and ECSprocedures. For ECoG mapping, the broadband gamma signal at each contactlocation was measured and compared between rest and task epochs toestablish the statistical difference across these tasks. See Brunner etal. (2009) Epilepsy & Behavior, 15: 278-286. The patient first restedquietly for six minutes to establish a model of baseline ECoG activity.The patient then performed several repetitive motor and language tasksas instructed by visual cues: 1) solve Rubik's cube; 2) shrug shoulders;3) stick out tongue; 4) purse lips; 5) listen to a narrative; 6)generate verbs; and 7) imagine generating verbs. This ECoG paradigmidentified electrode contacts 11 and 12 (FIG. 7A) as expressive languagenodes within a few minutes.

For the ECS procedure, a digital Grass 512X stimulator with built-instimulus isolation and constant current circuitry [Grass Technologies,Warwick, RI] was used to stimulate pairs of electrodes using a pulseduration of 0.3 ms, variable frequencies between 20-50 Hz, currentranging from 1-15 mA and train durations of 5 s. Bipolar and monopolarmodalities were assessed with increasing current until after-dischargesor a functional response was elicited, or the maximum amount of currentwas reached at 15 mA. Stimulation of contacts 11 and 12 with 10 mA at 20Hz rendered complete speech arrest, indicating eloquence. These nodeswere confirmed on four separate occasions throughout the procedure. Oralmotor function was also identified. An electrographic seizure waselicited with stimulation of contacts 23 and 41 during mapping; thepatient was treated with 2 mg IV Ativan, 1000 mg IV Keppra and 500 mgFosphenytoin. Further mapping was delayed for approximately 90 minutesdue to the stimulus-induced seizure and subsequent postictal period.

For a second stage operation, five days after the initial subdural gridimplantation, the patient returned to the operating room for the secondstage. Once the previous craniotomy flap was reopened and the corticalsurface was exposed with good hemostasis, the standard subdural grid wasreplaced with a high-density 64-contact silicon grid (PMT Corp.,Chanhassen, MN), measuring 2.5×2.5 cm embedded with platinum iridiumelectrodes of 2 mm diameter (1 mm exposed) and with an interelectrodedistance of 3 mm (FIGS. 6C and 6D). To further refine the boundary ofexpressive language function, this high-density grid covered only thelanguage cortex previously identified by extraoperative ECoG and ECSmapping. The patient was reversed from anesthesia for awake passivemapping. Within minutes, intraoperative ECoG mapping using verbgeneration and word repetition identified the most significant ECoGchanges at locations corresponding to contacts 11 and 12 of the originalstandard subdural grid. These locations were outlined for preservation.The patient tolerated the procedure very well and was induced back underanesthesia for the remainder of the surgery.

Postoperatively, the patient experienced an excellent recovery and hadvery mild issues of transient confusion. Permanent pathology revealedfocal anaplasia WHO III in the setting of diffuse fibrillary astrocytomaWHO II.

Mapping results from fMRI, ECS, and extra- and intraoperative ECoG aresummarized in FIGS. 7A-7D. For fMRI data acquisition, preoperative scanswere acquired on a Philips Ingenia 3T scanner with an echo planarimaging (EPI) sequence (80 scans, acquisition voxel size 3 mm isotropic,repetition time (TR) 3 s, echo time (TE) 30 ms, flip angle 90 degrees,field of view (FOV) 237 mm). Functional MRI data were preprocessed andanalyzed using statistical parametric mapping software (SPM8,http://www.fil.ion.ucl.ac.uk/spm). Images were re-aligned andco-registered with an anatomical scan using normalized mutualinformation. Statistical analyses were performed on a single-subjectbasis and therefore no smoothing was applied. A general linear model wasestimated with one regressor for verb generation (a 15 s box car forverb generation blocks convolved with a standard hemodynamic responsefunction), data were corrected for low frequency drifts by a 128 s highpass filter and corrected for serial correlations with a first-orderautoregressive model. Functional MRI results were rendered on thesurface of the cortex (FIG. 7B) in similar manner as publishedpreviously, plotting any activation up to 8 mm below the surface.Functional MRI activity was plotted with a threshold of t(150)>5.51,pFWEcorrected<0.05.

A three-dimensional patient-specific cortical surface brain model wascreated by submitting the preoperative high resolution MM scans toFreesurfer (http://surfer.nmr.mgh.harvard.edu). The stereotacticcoordinates of the standard subdural grid were identified using SPM8software (http://www.fil.ion.ucl.ac.uk/spm/) and custom MATLAB scripts(The MathWorks Inc., Natick, MA), which co-registered the MRI scans withthe postoperative CT scans. The high-density subdural grid contacts wereco-registered with those of the standard subdural grid using scalpfiducial markers, an intraoperative neuronavigation system (BrainLab AG,Feldkirchen, Germany) and novel custom software. The electrode locationswere then projected onto a three-dimensional brain model and customNeuralAct software (FIG. 7C) to render activation maps of correspondingECoG activity. ECS and extraoperative ECoG delineated identical criticallanguage nodes using a standardized grid coordinate system (FIG. 7C).The same locations were confirmed with intraoperative high-resolutionECoG (FIG. 7D). These results demonstrate the value of passiveECoG-based mapping in the extraoperative as well as the intraoperativeenvironment.

In another example, testing was conducted to map brain areas responsiblefor sensory function, according to recording methods as described above.FIG. 8 illustrates the result of ECoG-based brain mapping of brain areasresponsible for sensory function of the index finger in a subject. Asshown in FIG. 8 , each dot represents one electrode. The diameter ofeach electrode is proportional to the change in ECoG amplitude in thegamma (i.e., >70 Hz) range between rest and sensory stimulation. Thelocations identified using this procedure are similar to when thepatient was awake (FIG. 8 , top) compared to when the patient was underanesthesia (FIG. 8 , bottom). The magnitude of the effect (see colorbars) is noticeably smaller during anesthesia. These results demonstratethe importance of using ECoG to map brain areas responsible forsensorimotor functions in anesthetized or unresponsive patients in aperioperative setting.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be understood that the terms “comprise”, “have”,“include”, and “contain” (and any related variants thereof) areopen-ended linking verbs. As a result, a method, step, or device that“comprises”, “has”, “includes” or “contains” one or more steps orelements possesses those one or more steps or elements, but is notlimited to possessing only those one or more steps or elements. Thecorresponding structures, materials, acts, and equivalents of all meansor step plus function elements in the claims below, if any, are intendedto include any structure, material, or act for performing the functionin combination with other claimed elements as specifically claimed. Thedisclosure herein is illustrative and not intended to be exhaustive orlimited to the invention in the form disclosed. Many modifications andvariations will be apparent to those of ordinary skill in the artwithout departing from the scope and spirit of the invention.Embodiments are described to best explain the principles of one or moreaspects of the invention and the practical application, and to enableothers of ordinary skill in the art to understand one or more aspects ofthe invention for various embodiments with various modifications as aresuited to the particular use contemplated.

What is claimed is:
 1. A method for mapping a neural area involved inspeech processing comprising: applying a plurality of recordingelectrodes to a surface of a cortex of a human subject; presenting aplurality of auditory stimuli to the subject wherein at least one of theplurality of auditory stimuli comprises a non-scrambled speech sound andat least one of the plurality of auditory stimuli comprises a scrambledspeech sound; recording from at least one brain area a first brainactivity and a second brain activity, wherein the first brain activitycomprises a change during the presenting of the non-scrambled speechsound and the second brain activity comprises a change during thepresenting of the scrambled speech sound; and identifying one or more ofthe at least one brain area wherein the change during the presenting ofthe non-scrambled speech sound is greater than the change during thepresenting of the scrambled speech sound; wherein the human subject isunconscious during the presenting and the recording.
 2. The method ofclaim 1, wherein the human subject is anesthetized during the presentingand the recording.
 3. The method of claim 2, wherein one or more of theplurality of recording electrodes includes a diameter of an exposedsurface of approximately 1 cm.
 4. The method of claim 2, wherein one ormore change during the presenting in one or more of the at least onebrain area occurs within between 250-750 ms after an onset of thepresenting of one or both of the non-scrambled speech sound and thescrambled speech sound.
 5. The method of claim 2, wherein recordingcomprises making an analog recording and identifying comprisesconverting the analog recording to a digital recording and identifyingone or more of the at least one brain area wherein power of thebroadband gamma waves changes more after the presenting of thenon-scrambled speech sound than it does after the presenting of thescrambled speech sound.
 6. The method of claim 1, further comprisingmapping a neural area involved in speech production, wherein applyingthe plurality of recording electrodes comprises applying at least one ofthe plurality of electrodes to a surface of a frontal cortex of thehuman subject.
 7. The method of claim 1, further comprising mapping aneural area involved in speech reception, wherein applying the pluralityof recording electrodes comprises applying at least one of the pluralityof electrodes to a surface of a temporal cortex of the human subject. 8.The method of claim 1, wherein one or more of the plurality of recordingelectrodes includes a diameter of an exposed surface of less thanapproximately 2.5 mm.
 9. The method of claim 8, wherein one or more ofthe plurality of recording electrodes includes a diameter of an exposedsurface of approximately 1 mm.
 10. The method of claim 1, whereinapplying the plurality of recording electrodes comprises applying withan inter-electrode distance of 1 cm or less.
 11. The method of claim 10,wherein applying the plurality of recording electrodes comprisesapplying with an inter-electrode distance of 3 mm or less.
 12. Themethod of claim 1, wherein one or more change during the presenting inone or more of the at least one brain area occurs within between100-1000 ms after an onset of the presenting of one or both of thenon-scrambled speech sound and the scrambled speech sound.
 13. Themethod of claim 12, wherein one or more change during the presenting inone or more of the at least one brain area occurs within between 250-750ms after an onset of the presenting of one or both of the non-scrambledspeech sound and the scrambled speech sound.
 14. The method of claim 1,wherein the change during the presenting of the non-scrambled speechsound in one or more of the at least one brain area occurs for aduration that is shorter than a duration of the presenting of thenon-scrambled speech sound.
 15. The method of claim 14, wherein theduration of the presenting of the non-scrambled speech sound is within arange of from 1000 ms to 120,000 ms.
 16. The method of claim 15, whereinthe duration of the presenting of the non-scrambled speech sound rangesfrom about 1000 ms to about 50,000 ms.
 17. The method of claim 1,wherein the change during the presenting of the non-scrambled speechsound in one or more of the at least one brain area occurs forsubstantially all of a duration of the presenting of the non-scrambledspeech sound.
 18. The method of claim 1, wherein recording comprisesrecording broadband gamma waves.
 19. The method of claim 18, whereinidentifying comprises identifying one or more of the at least one brainarea wherein power of the broadband gamma waves changes more during thepresenting of the non-scrambled speech sound than it does during thepresenting of the scrambled speech sound.
 20. The method of claim 1,wherein recording the first brain activity and the second brain activitycomprises recording oscillatory activity and the oscillatory activity isone or more of theta, alpha, or beta activity.
 21. The method of claim1, wherein recording the first brain activity and the second brainactivity comprises recording evoked potential activity.
 22. The methodof claim 1, wherein recording comprises making an analog recording andidentifying comprises converting the analog recording to a digitalrecording.
 23. The method of claim 22, further comprising using ahardware processor to control the time of onset of the plurality ofauditory stimuli and to measure the first brain activity and the secondbrain activity.
 24. The method of claim 23, wherein identifyingcomprises identifying one or more of the at least one brain area whereinpower of the broadband gamma waves of one or more of the at least onebrain area changes more after the presenting of the non-scrambled speechsound than it does after the presenting of the scrambled speech sound.25. A method for mapping a neural area involved in speech productioncomprising: applying a plurality of recording electrodes to a surface ofa cortex of a human subject; presenting a plurality of auditory stimulito the subject wherein at least one of the plurality of auditory stimulicomprises a non-scrambled speech sound and at least one of the pluralityof auditory stimuli comprises a scrambled speech sound; recording fromat least one brain area a first brain activity and a second brainactivity, wherein the first brain activity comprises a change during thepresenting of the non-scrambled speech sound and the second brainactivity comprises a change during the presenting of the scrambledspeech sound; and identifying one or more of the at least one brain areawherein the change during the presenting of the non-scrambled speechsound is greater than the change during the presenting of the scrambledspeech sound; wherein the human subject is unconscious during thepresenting and the recording.